PROJECT SUMMARY/ABSTRACT The COVID-19 pandemic has high potential to lead to broad increases in substance use among pregnant women (e.g., via increased social isolation and loneliness due to extensive ?shelter-in-place? orders, psychological and financial distress, fear of infection). Further, smoking, vaping and other substance use may increase risk for COVID-19 and its more serious complications; pregnant women are an ideal population to study the effects of substance use on COVID-19 risk and illness progression as they have reduced immune functioning and, in Kaiser Permanente Northern California (KPNC), are routinely screened for substance use as part of standard prenatal care. The proposed study represents an unparalleled opportunity to efficiently leverage rich, valid and contemporary prenatal substance use data by self-report and urine toxicology testing from our existing R01 study (DA047405) in innovative ways. For Aim 1, we take advantage of a unique natural experiment using interrupted time series analyses to examine whether the COVID-19 pandemic is associated with broad increases in prenatal substance use overall and among vulnerable subsets of pregnant women (e.g., those with prenatal depression, low socioeconomic status (SES)) using data from ~200,000 pregnancies universally screened for prenatal substance from January 2018 to December 2021. For Aim 2, we will conduct a retrospective and prospective longitudinal cohort study of ~100,000 pregnant women from January 2020 to December 2021, to examine whether substance use in the year before pregnancy, and during pregnancy, is associated with increased risk of COVID-19 onset and severity of illness. COVID-19 data will be ascertained from KPNC?s innovative tracking and surveillance system which includes laboratory confirmed COVID-19 infection, persons under investigation with symptoms who have not yet been tested, symptom severity, medical complications, and mortality. These data will be efficiently linked to prenatal substance use data ascertained for the parent grant using the electronic health record with high generalizability and a large sample size. Our results will provide sorely needed and generalizable data on the impact of this pandemic on rates of prenatal substance use and the impact of substance use on COVID-19 onset and progression. Results will guide preventive measures, public health interventions, and health services, and can inform best practices to protect pregnant women against potential long-term health consequences of this pandemic.